Asymmetric organocatalytic synthesis of 4,6-bis(1H-indole-3-yl)-piperidine-2 carboxylates

Abstract

We developed an asymmetric organocatalytic synthesis of 4,6-bis(1H-indole-3-yl)-piperidine-2-carboxylates using 10 mol% of a chiral phosphoric acid. The products, which are novel bisindole-piperidine-amino acid hybrids, can be obtained in one step from 3-vinyl indoles with imino esters in dichloromethane at room temperature after 1 h of reaction time. A variety of these compounds could be synthesized in up to 70% yield and 99% ee, and they were experimentally and computationally analyzed regarding their relative and absolute stereochemistry.

Asymmetric Organocatalytic Synthesis of Bisindoles – Scope and Derivatizations

“…But employing these catalysts did not lead to satisfying results. There was almost no enantioinduction (7.5 % ee ) observed and the yields were mostly diminished compared to those without applying any catalyst . Therefore we chose another widely used catalyst class in organic chemistry – chiral phosphoric acids, also used by Ricci et al in the aforementioned paper .…”

“…The relative configuration was identified through NOE correlations (Figure ). In a previous study, we could prove the configuration (2 S ,4 S ,6 S ) through NOE correlation experiments, X‐ray crystallography and electronic circular dichroism (CD) spectroscopy . Therefore we performed a NOE correlation with F2 of bisindole 5gg .…”

“…Recently we developed a powerful enantioselective organocatalyzed three‐component synthesis of 4,6‐bis(1 H ‐indole‐3‐yl)piperidine 2‐carboxylates ( 5 ) utilizing easily accessible 3‐vinylindoles ( 3 ) and imino esters ( 4 ) and a chiral phosphoric acid (Scheme ) . The reaction proceeds diastereoselectively within 1 h at room temperature by building three new bonds and three new stereogenic centers in one step.…”

“…An intramolecular ring closure of 6 finally yields ( rac )‐ 5aa as product. To proceed the reaction, a free NH group on the indole moiety is necessary, as in previous studies with N ‐methylated derivatives no product could be isolated …”

Catalytic Asymmetric Aza‐Diels‐Alder Reaction: Pivotal Milestones and Recent Applications to Synthesis of Nitrogen‐Containing Heterocycles

“…The authors managed to trap the primary iminium intermediate Int 22 with external nucleophile such as arylamine PMPNH 2 or the second 3‐vinylindole molecule. Corresponding products 229 or 230 of high enantiomeric purity were isolated in good yield as a mixture of diastereomers (for the asymmetric synthesis of a diverse library of 2,4‐ bis (indol‐3‐yl)piperidine derivatives via the interrupted Povarov reaction of glyoxylate arylaldimines with 3‐vinylindoles catalyzed by chiral phosphoric acids refer to [238,239] ).…”